PROJECT SUMMARY Tuberculosis (TB) remains a leading cause of death globally, particularly among HIV-positive people. Understanding the dynamics of TB transmission in the era of antiretroviral therapy (ART) is key to halting TB transmission. As ART roll-out progresses, whether the contribution of people taking ART to TB transmission is increasing is unknown. Community TB surveys consistently show that about half of people with infectious TB do not report symptoms, and are therefore missed by most current TB screening efforts. The objective of this project is define how to target TB case-finding efforts to maximise impact while retaining cost-effectiveness, in settings of high HIV prevalence and mature ART programs. Our central hypothesis is that populations and settings can be defined where symptom-agnostic TB screening (i.e. not limited to symptomatic people) has a major impact on TB transmission, and is cost-effective. The project aims are (1) to compare the infectiousness of HIV-positive people taking ART compared to those not taking ART; (2) to assess the infectiousness of the walking well, i.e. people with asymptomatic TB; (3) to model the impact and cost-effectiveness of symptom- agnostic screening at different levels of the health system. The project will be conducted in the context of the Africa Health Research Institute (AHRI)'s demographic surveillance area in KwaZulu-Natal, South Africa where TB incidence, HIV prevalence and ART coverage are high, and a population survey using mass radiographic screening for TB has started. We will accomplish our aims through a household contact study, measuring the proportion of child household contacts who have TB infection, comparing groups of households according to characteristics of the index TB patient. For Aim 1, we will compare the proportion of child contacts with TB infection between HIV-positive index TB patients who are vs. are not taking ART. For Aim 2, we will compare the proportion of child contacts with TB infection between asymptomatic index TB patients who do not report any symptoms (identified by AHRI's population TB survey) vs. symptomatic index TB patients. This gives us a unique opportunity to investigate TB transmission from people who do not report TB symptoms, who are missed by most TB screening programs. In Aim 3 we will use a novel mathematical model, incorporating new insights into TB natural history and transmission gained from Aims 1 and 2, to determine the circumstances under which symptom-agnostic screening would have most impact on TB incidence and mortality, and explore comparative cost-effectiveness of interventions along the diagnostic pathway at different levels of the health system. By combining population-based epidemiology with mathematical and economic modelling, our project will delineate (i) whether more resources should be dedicated to earlier identification of TB among people taking ART; (ii) whether symptom-agnostic screening of the walking well; should be considered and (iii) under what conditions. This could inform a paradigm shift in TB case-finding strategy.